Novel use of peptide compounds for treating amyotrophic lateral sclerosis

ABSTRACT

The present invention is directed to the use of a class of peptide compounds for treating amyotrophic lateral sclerosis (ALS) and other forms of motoneuron diseases and peripheral neuropathies.

The present invention is directed to the use of a class of peptidecompounds for treating amyotrophic lateral sclerosis (ALS) and otherforms of motoneuron diseases and peripheral neuropathies.

Certain peptides are known to exhibit central nervous system (CNS)activity and are useful in the treatment of epilepsy and other CNSdisorders. These peptides which are described in the U.S. Pat. No.5,378,729 have the Formula (Ia):

whereinR is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl, aryllower alkyl, heterocyclic, heterocyclic lower alkyl, lower alkylheterocyclic, lower cycloalkyl, lower cycloalkyl lower alkyl, and R isunsubstituted or is substituted with at least one electron withdrawinggroup or electron donating group;R₁ is hydrogen or lower alkyl, lower alkenyl, lower alkynyl, aryl loweralkyl, aryl, heterocyclic lower alkyl, heterocyclic, lower cycloalkyl,lower cycloalkyl lower alkyl, each unsubstituted or substituted with anelectron donating group or an electron withdrawing group; andR₂ and R₃ are independently hydrogen, lower alkyl, lower alkenyl, loweralkynyl, aryl lower alkyl, aryl, heterocyclic, heterocyclic lower alkyl,lower alkyl heterocyclic, lower cycloalkyl, lower cycloalkyl loweralkyl, or Z-Y wherein R₂ and R₃ may be unsubstituted or substituted withat least one electron withdrawing group or electron donating group;Z is O, S, S(O)_(a), NR₄, PR₄ or a chemical bond;Y is hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl, loweralkynyl, halo, heterocyclic, heterocyclic lower alkyl, and Y may beunsubstituted or substituted with an electron donating group or anelectron withdrawing group, provided that when Y is halo, Z is achemical bond, orZY taken together is NR₄NR₅R₇, NR₄O₅, ONR₄R₇, OPR₄R₅, PR₄OR₅, SNR₄R₇,NR₄SR₇, SPR₄R₅ or PR₄SR₇, NR₄PR₅R₆ or PR₄NR₅R₇,

R₄, R₅ and R₆ are independently hydrogen, lower alkyl, aryl, aryl loweralkyl, lower alkenyl, or lower alkynyl, wherein R₄, R₅ and R₆ may beunsubstituted or substituted with an electron withdrawing group or anelectron donating group; andR₇is R₆ or COOR₈ or CON;R₈ is hydrogen or lower alkyl, or aryl lower alkyl, and the aryl oralkyl group may be unsubstituted or substituted with an electronwithdrawing group or an electron donating group; andn is 1-4; anda is 1-3.

U.S. Pat. No. 5,773,475 also discloses additional compounds useful fortreating CNS disorders. These compounds areN-benzyl-2-amino-3-methoxy-propionamide having the Formula (IIa):

whereinAr is aryl which is unsubstituted or substituted with halo; R₃ is loweralkoxy; and R₁ is methyl.

The patents U.S. Pat. No. 5,378,729 and U.S. Pat. No. 5,773,475 arehereby incorporated by reference. However, neither of these patentsdescribes the use of these compounds as specific neuroprotective agentsfor the treatment of ALS and other motoneuron diseases as well asperipheral neuropathies.

WO 02/074297 relates to the use of a compound according to Formula (IIa)wherein Ar is phenyl which may be substituted by at least one halo, R₃is lower alkoxy containing 1-3 carbon atoms and R₁ is methyl for thepreparation of pharmaceutical compositions useful for the treatment ofallodynia related to peripheral neuropathic pain.

WO 02/074784 relates to the use of a compound having Formula (Ia) or/andFormula (IIa) showing antinociceptive properties for treating differenttypes and symptoms of acute and chronic pain, especially non neuropathicinflammatory pain, e.g. rheumatoid arthritic pain or/and secondaryinflammatory osteo-arthritic pain.

Amyotrophic lateral sclerosis is characterized by degeneration and lossof motoneurons in the anterior horn of the spinal cord and of thebrainstem and, to a variable extent, by degeneration of the descendingmotor pathways within the cortico-spinal tract (Deng et al., 1993;Rothstein et al., 1995). This disorder leads to progressive muscularatrophy, weakness, paralysis and eventually death due to respiratoryfailure (Andersen et al., 1995). ALS occurs in both familial (FALS) andsporadic (SALS) forms. FALS accounts for 5-10% of cases, with anautosomal dominant pattern of inheritance (Gurney et al., 1994; Rosen etal., 1993). Approximately 20% of the FALS cases have been associatedwith mutations in SOD1, the gene that encodes for cytosolic Cu,Znsuperoxide dismutase (SOD) (Beckman et al., 1993; Rosen et al., 1993).This recent discovery of mutations affecting the SOD gene has givenimpetus to research on the role of oxidative stress in the pathogenesisof FALS.

In order to establish an animal model for familial ALS, several strainsof transgenic mice that carry the human SOD1 gene have been produced.Mice overproducing wild-type human Cu,Zn SOD are clinically normal andin fact show increased resistance to oxidative stress (Yang et al.,1994). Mice producing mutant Cu,Zn SOD rapidly develop a progressivemotoneuron disease that strongly resembles ALS (Gurney et al., 1994;Mohajeri et al., 1998). This phenotype occurs in mice expressing theG93A mutation as well as a glycine→arginine mutation (Gurney et al.,1994).

The mechanisms of motoneuron disorders are poorly understood. Currenttreatments use a variety of pharmacological, surgical, physical andpsychological approaches. However, the evidence for many of thetreatments is still limited.

The use of compounds of Formula (Ib) or/and Formula (IIb) for treatmentof motoneuron disorders has not been reported. Thus, the presentinvention concerns the use of said compounds of Formulae (Ib) or/and(IIb) for the preparation of a pharmaceutical composition for theprevention, alleviation or/and treatment of motoneuron disorders such asALS, progressive spinal muscular atrophies or progressive bulbar palsy,or/and peripheral neuropathies such as Guillain-Barré Syndrome orCharcot-Marie-Tooth Syndrome.

Surprisingly, application of compounds (Ib) or/and (IIb), particularly(R)-2-acetamide-N-benzyl-3-methoxypropionamide (SPM 927) exhibited asignificant efficacy in prolonging survival and improving motorcoordination in mice suffering from motor neuron diseases. Thus, thecompounds are useful as medicaments for motoneuron disorders orperipheral neuropathies.

A compound according to the invention has the general Formula (Ib)

whereinR is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl, aryllower alkyl, heterocyclic, heterocyclic lower alkyl, lower alkylheterocyclic, lower cycloalkyl or lower cycloalkyl lower alkyl, and R isunsubstituted or is substituted with at least one electron withdrawinggroup, and/or at least one electron donating group;R₁ is hydrogen or lower alkyl, lower alkenyl, lower alkynyl, aryl loweralkyl, aryl, heterocyclic lower alkyl, lower alkyl heterocyclic,heterocyclic, lower cycloalkyl, lower cycloalkyl lower alkyl, eachunsubstituted or substituted with at least one electron donating groupand/or at least one electron withdrawing group;andR₂ and R₃ are independently hydrogen, lower alkyl, lower alkenyl, loweralkynyl, aryl lower alkyl, aryl, halo, heterocyclic, heterocyclic loweralkyl, lower alkyl heterocyclic, lower cycloalkyl, lower cycloalkyllower alkyl, or Z-Y wherein R₂ and R₃ may be unsubstituted orsubstituted with at least one electron withdrawing group and/or at leastone electron donating group;Z is O, S, S(O)_(a), NR₄, NR′₆, PR₄or a chemical bond;Y is hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl, loweralkynyl, halo, heterocyclic, heterocyclic lower alkyl, lower alkylheterocyclic and Y may be unsubstituted or substituted with at least oneelectron donating group and/or at least one electron withdrawing group,provided that when Y is halo, Z is a chemical bond, orZY taken together is NR₄NR₅R₇, NR₄O₅, ONR₄R₇, OPR₄R₅, PR₄O₅, SNR₄R₇,NR₄SR₇, SPR₄R₅, PR₄SR₇, NR₄PR₅R₆, PR₄NR₅R₇ or N⁺R₅R₆R₇,

R′₆ is hydrogen, lower alkyl, lower alkenyl, or lower alkenyl which maybe unsubstituted or substituted with at least one electron withdrawinggroup or/and at least one electron donating group;R₄, R₅ and R₆ are independently hydrogen, lower alkyl, aryl, aryl loweralkyl, lower alkenyl, or lower alkynyl, wherein R₄, R₅ and R₆ mayindependently be unsubstituted or substituted with at least one electronwithdrawing group or/and at least one electron donating group;R₇ is R₆ or COOR₈ or COR₈, which R₇ may be unsubstituted or substitutedwith at least one electron withdrawing group or/and at least oneelectron donating group;R₈ is hydrogen or lower alkyl, or aryl lower alkyl, and the aryl oralkyl group may be unsubstituted or substituted with at least oneelectron withdrawing group or/and at least one electron donating group;andn is 1-4; anda is 1-3.

Preferably the compound according has the general Formula (IIb)

whereinAr is aryl, especially phenyl, which is unsubstituted or substitutedwith at least one halo; R₃is —CH₂-Q, wherein Q is lower alkoxy; and R₁is lower alkyl, especially methyl.

The present invention is also directed to a pharmaceutical compositioncomprising a compound according to Formula (Ib) or/and Formula (IIb)useful for the prevention, alleviation or/and treatment of motoneurondisorders or/and peripheral neuropathies.

The “lower alkyl” groups when used alone or in combination with othergroups, are lower alkyl containing from 1 to 6 carbon atoms, especially1 to 3 carbon atoms, and may be straight chain or branched. These groupsinclude methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiarybutyl, amyl, hexyl, and the like.

The “lower alkoxy” groups are lower alkoxy containing from 1 to 6 carbonatoms, especially 1 to 3 carbon atoms, and may be straight chain orbranched. These groups include methoxy, ethoxy, propoxy, butoxy,isobutoxy, tert-butoxy, pentoxy, hexoxy and the like.

The “aryl lower alkyl” groups include, for example, benzyl, phenylethyl,phenylpropyl, phenylisopropyl, phenylbutyl, diphenylmethyl,1,1-diphenylethyl, 1,2-diphenylethyl, and the like.

The term “aryl”, when used alone or in combination, refers to anaromatic group which contains from 6 up to 18 ring carbon atoms and upto a total of 25 carbon atoms and includes the polynuclear aromatics.These aryl groups may be monocyclic, bicyclic, tricyclic or polycyclicand are fused rings. A polynuclear aromatic compound as used herein, ismeant to encompass bicyclic and tricyclic fused aromatic ring systemscontaining from 10-18 ring carbon atoms and up to a total of 25 carbonatoms. The aryl group includes phenyl, and the polynuclear aromaticse.g., naphthyl, anthracenyl, phenanthrenyl, azulenyl and the like. Thearyl group also includes groups like ferrocenyl. Aryl groups may beunsubstituted or mono or polysubstituted with electron withdrawingor/and electron donating groups as described below.

“Lower alkenyl” is an alkenyl group containing from 2 to 6 carbon atomsand at least one double bond. These groups may be straight chained orbranched and may be in the Z or E form. Such groups include vinyl,propenyl, 1-butenyl, isobutenyl, 2-butenyl, 1-pentenyl, (Z)-2-pentenyl,(E)-2-pentenyl, (Z)-4-methyl-2-pentenyl, (E)-4-methyl-2-pentenyl,pentadienyl, e.g., 1, 3 or 2,4-pentadienyl, and the like.

The term “lower alkynyl” is an alkynyl group containing 2 to 6 carbonatoms and may be straight chained as well as branched. It includes suchgroups as ethynyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl,2-pentynyl, 3-methyl-1-pentynyl, 3-pentynyl, 1-hexynyl, 2-hexynyl,3-hexynyl and the like.

The term “lower cycloalkyl” when used alone or in combination is acycloalkyl group containing from 3 to 18 ring carbon atoms and up to atotal of 25 carbon atoms. The cycloalkyl groups may be monocyclic,bicyclic, tricyclic, or polycyclic and the rings are fused. Thecycloalkyl may be completely saturated or partially saturated. Examplesinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, cyclodecyl, cyclohexenyl, cyclopentenyl, cyclooctenyl,cycloheptenyl, decalinyl, hydroindanyl, indanyl, fenchyl, pinenyl,adamantyl, and the like. Cycloalkyl includes the cis or trans forms.Cycloalkyl groups may be unsubstituted or mono or polysubstituted withelectron withdrawing or/and electron donating groups as described below.Furthermore, the substituents may either be in endo or exo positions inthe bridged bicyclic systems.

The term “electron-withdrawing and electron donating” refer to theability of a substituent to withdraw or donate electrons, respectively,relative to that of hydrogen if the hydrogen atom occupied the sameposition in the molecule. These terms are well understood by one skilledin the art and are discussed in Advanced Organic Chemistry, by J. March,John Wiley and Sons, New York, N.Y., pp. 16-18 (1985) and the discussiontherein is incorporated herein by reference. Electron withdrawing groupsinclude halo, including bromo, fluoro, chloro, iodo and the like; nitro,carboxy, lower alkenyl, lower alkynyl, formyl, carboxyamido, aryl,quaternary ammonium, haloalkyl such as trifluoromethyl, aryl loweralkanoyl, carbalkoxy and the like. Electron donating groups include suchgroups as hydroxy, lower alkoxy, including methoxy, ethoxy and the like;lower alkyl, such as methyl, ethyl, and the like; amino, loweralkylamino, di(loweralkyl) amino, aryloxy such as phenoxy, mercapto,lower alkylthio, lower alkylmercapto, disulfide (lower alkyldithio) andthe like. One of ordinary skill in the art will appreciate that some ofthe aforesaid substituents may be considered to be electron donating orelectron withdrawing under different chemical conditions. Moreover, thepresent invention contemplates any combination of substituents selectedfrom the above-identified groups.

The term “halo” includes fluoro, chloro, bromo, iodo and the like.

The term “acyl” includes lower alkanoyl containing from 1 to 6 carbonatoms and may be straight chains or branched. These groups include, forexample, formyl, acetyl, propionyl, butyryl, isobutyryl, tertiarybutyryl, pentanoyl and hexanoyl.

As employed herein, a heterocyclic group contains at least one sulfur,nitrogen or oxygen ring atom, but also may include several of said atomsin the ring. The heterocyclic groups contemplated by the presentinvention include heteroaromatics and saturated and partially saturatedheterocyclic compounds. These heterocyclics may be monocyclic, bicyclic,tricyclic or polycyclic and are fused rings. They may preferably containup to 18 ring atoms and up to a total of 17 ring carbon atoms and atotal of up to 25 carbon atoms. The heterocyclics are also intended toinclude the so-called benzoheterocyclics. Representative heterocyclicsinclude furyl, thienyl, pyrazolyl, pyrrolyl, methylpyrrolyl, imidazolyl,indolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, piperidyl,pyrrolinyl, piperazinyl, quinolyl, triazolyl, tetrazolyl, isoquinolyl,benzofuryl, benzothienyl, morpholinyl, benzoxazolyl, tetrahydrofuryl,pyranyl, indazolyl, purinyl, indolinyl, pyrazolindinyl, imidazolinyl,imadazolindinyl, pyrrolidinyl, furazanyl, N-methylindolyl, methylfuryl,pyridazinyl, pyrimidinyl, pyrazinyl, pyridyl, epoxy, aziridino,oxetanyl, azetidinyl, the N-oxides of the nitrogen containingheterocycles, such as the N-oxides of pyridyl, pyrazinyl, andpyrimidinyl and the like. Heterocyclic groups may be unsubstituted ormono or polysubstituted with electron withdrawing or/and electrondonating groups.

The preferred heterocyclics are thienyl, furyl, pyrrolyl, benzofuryl,benzothienyl, indolyl, methylpyrrolyl, morpholinyl, pyridiyl, pyrazinyl,imidazolyl, pyrimidinyl, or pyridazinyl. The preferred heterocyclic is a5 or 6-membered heterocyclic compound. The especially preferredheterocyclic is furyl, pyridyl, pyrazinyl, imidazolyl, pyrimidinyl, orpyridazinyl. The most preferred heterocyclics are furyl and pyridyl.

The preferred compounds are those wherein n is 1, but di (n=2), tri(n=3) and tetrapeptides (n=4) are also contemplated to be within thescope of the invention.

The preferred values of R is aryl lower alkyl, especially benzylespecially those wherein the phenyl ring thereof is unsubstituted orsubstituted with electron donating groups or/and electron withdrawinggroups, such as halo (e.g., F).

The preferred R₁ is H or lower alkyl. The most preferred R₁ group ismethyl.

The preferred electron donating substituents or/and electron withdrawingsubstituents are halo, nitro, alkanoyl, formyl, arylalkanoyl, aryloyl,carboxyl, carbalkoxy, carboxamido, cyano, sulfonyl, sulfoxide,heterocyclic, guanidine, quaternary ammonium, lower alkenyl, loweralkynyl, sulfonium salts, hydroxy, lower alkoxy, lower alkyl, amino,lower alkylamino, di(loweralkyl) amino, amino lower alkyl, mercapto,mercaptoalkyl, alkylthio, and alkyldithio. The term “sulfide”encompasses mercapto, mercapto alkyl and alkylthio, while the termdisulfide encompasses alkyldithio. Especially preferred electrondonating or/and electron withdrawing groups are halo or lower alkoxy,most preferred are fluoro or methoxy. These preferred substituents maybe present on any one of the groups in Formula (Ib) or/and (IIb), e.g.R, R₁, R₂, R₃, R₄, R₅, R₆, R′₆, R₇, R₈ and/or R₅₀ as defined herein.

The ZY groups representative of R₂ and R₃ include hydroxy, alkoxy, suchas methoxy, ethoxy, aryloxy, such as phenoxy; thioalkoxy, such asthiomethoxy, thioethoxy; thioaryloxy such as thiophenoxy; amino;alkylamino, such as methylamino, ethylamino; arylamino, such as anilino;lower dialkylamino, such as, dimethylamino; trialkyl ammonium salt,hydrazino; alkylhydrazino and arylhydrazino, such as N-methylhydrazino,N-phenylhydrazino, carbalkoxy hydrazino, aralkoxycarbonyl hydrazino,aryloxycarbonyl hydrazino, hydroxylamino, such as N-hydroxylamino(—NH—OH), lower alkoxy amino [(NHOR₁₈) wherein R₁₈ is lower alkyl],N-lower alkylhydroxyl amino [(NR₁₈)OH wherein R₁₈ is lower alkyl],N-lower alkyl-O-lower alkylhydroxyamino, i.e., [N(R₁₈)OR₁₉ wherein R₁₈and R₁₉ are independently lower alkyl], and o-hydroxylamino (—O—NH₂);alkylamido such as acetamido; trifluoroacetamido; lower alkoxyamino,(e.g., NH(OCH₃); and heterocyclicamino, such as pyrazoylamino.

The preferred heterocyclic groups representative of R₂ and R₃ aremonocyclic 5- or 6-membered heterocyclic moieties of the formula:

or those corresponding partially or fully saturated form thereof whereinn is 0 or 1; andR₅₀ is H or an electron withdrawing group or electron donating group;A, E, L, J and G are independently CH, or a heteroatom selected from thegroup consisting of N, O, S;but when n is 0, G is CH, or a heteroatom selected from the groupconsisting of NO, O and S with the proviso that at most two of A, E, L,J and G are heteroatoms.

When n is 0, the above heteroaromatic moiety is a five membered ring,while if n is 1, the heterocyclic moiety is a six membered monocyclicheterocyclic moiety. The preferred heterocyclic moieties are thoseaforementioned heterocyclics which are monocyclic.

If the ring depicted hereinabove contains a nitrogen ring atom, then theN-oxide forms are also contemplated to be within the scope of theinvention.

When R₂ or R₃is a heterocyclic of the above formula, it may be bonded tothe main chain by a ring carbon atom. When n is 0, R₂ or R₃ mayadditionally be bonded to the main chain by a nitrogen ring atom.

Other preferred moieties of R₂ and R₃ are hydrogen, aryl, e.g., phenyl,aryl alkyl, e.g., benzyl and alkyl.

It is to be understood that the preferred groups of R₂ and R₃ may beunsubstituted or mono or poly substituted with electron donating or/andelectron withdrawing groups. It is preferred that R₂ and R₃ areindependently hydrogen, lower alkyl, which is either unsubstituted orsubstituted with electron withdrawing groups or/and electron donatinggroups, such as lower alkoxy (e.g., methoxy, ethoxy, and the like),N-hydroxylamino, N-lower alkylhydroxyamino, N-loweralkyl-O-loweralkyland alkylhydroxyamino.

It is preferred that one of R₂ and R₃ is hydrogen.

It is preferred that n is one.

It is more prefered that n=1 and one of R₂ and R₃ is hydrogen. It isespecially preferred that in this embodiment, R₂is hydrogen and R₃islower alkyl or ZY;

Z is O, NR₄ or PR₄; Y is hydrogen or lower alkyl; ZY is NR₄NR₅R₇,NR₄OR₅, ONR₄R₇,

In another especially preferred embodiment, n=1, R₂ is hydrogen and R₃is lower alkyl which may be substituted or unsubstituted with anelectron donating or electron withdrawing group, NR₄OR₅, or ONR₄R₇.

In yet another especially preferred embodiment, n=1, R₂ is hydrogen andR₃ is lower alkyl which is unsubstituted or substituted with hydroxy orloweralkoxy, NR₄OR₅ or ONR₄R₇, wherein R₄, R₅ and R₇ are independentlyhydrogen or lower alkyl, R is aryl lower alkyl, which aryl group may beunsubstituted or substituted with an electron withdrawing group and R₁is lower alkyl. In this embodiment it is most preferred that aryl isphenyl, which is unsubstituted or substituted with halo.

It is preferred that R₂is hydrogen and R₃is hydrogen, an alkyl groupwhich is unsubstituted or substituted by at least an electron donatingor electron withdrawing group or ZY. In this preferred embodiment, it ismore preferred that R₃ is hydrogen, an alkyl group such as methyl, whichis unsubstituted or substituted by an electron donating group, or NR₄O₅or ONR₄R₇, wherein R₄, R₅ and R₇ are independently hydrogen or loweralkyl. It is preferred that the electron donating group is lower alkoxy,and especially methoxy or ethoxy.

It is preferred that R₂ and R₃ are independently hydrogen, lower alkyl,or ZY;

Z is O, NR₄ or PR₄;

Y is hydrogen or lower alkyl or

ZY is NR₄R₅R₇, NR₄OR₅, ONR₄R₇,

It is also preferred that R is aryl lower alkyl. The most preferred arylfor R is phenyl. The most preferred R group is benzyl. In a preferredembodiment, the aryl group may be unsubstituted or substituted with anelectron donating or electron withdrawing group. If the aryl ring in Ris substituted, it is most preferred that it is substituted with anelectron withdrawing group, especially on the aryl ring. The mostpreferred electron withdrawing group for R is halo, especially fluoro.

The preferred R₁ is lower alkyl, especially methyl.

It is more preferred that R is aryl lower alkyl and R₁ is lower alkyl.

Further preferred compounds are compounds of Formula (Ib) wherein n is1; R₂ is hydrogen; R₃ is hydrogen, a lower alkyl group, especiallymethyl which is substituted by an electron donating or electronwithdrawing group or ZY; R is aryl, aryl lower alkyl, such as benzyl,wherein the aryl group is unsubstituted or substituted with an electrondonating or electron withdrawing group and R₁ is lower alkyl. In thisembodiment, it is more preferred that R₃ is hydrogen, a lower alkylgroup, especially methyl, which may be substituted by electron donatinggroup, such as lower alkoxy, (e.g., methoxy, ethoxy and the like),NR₄OR₅ or ONR₄R₇ wherein these groups are defined hereinabove.

The most preferred compounds utilized are those of the Formula (IIb):

whereinAr is aryl, especially phenyl, which is unsubstituted or substitutedwith at least one electron donating group or electron withdrawing group,especially halo,R₁ is lower alkyl, especially containing 1-3 carbon atoms; andR₃ is as defined herein, but especially hydrogen, loweralkyl, which isunsubstituted or substituted by at least an electron donating group orelectron withdrawing group or ZY. It is even more preferred that R₃ is,in this embodiment, hydrogen, an alkyl group which is unsubstituted orsubstituted by an electron donating group, NR₄OR₅ or ONR₄R₇. It is mostpreferred that R₃ is CH₂-Q, wherein Q is lower alkoxy, especiallycontaining 1-3 carbon atoms; NR₄OR₅ or ONR₄R₇ wherein R₄ is hydrogen oralkyl containing 1-3 carbon atoms, R₅ is hydrogen or alkyl containing1-3 carbon atoms, and R₇ is hydrogen or alkyl containing 1-3 carbonatoms.

The most preferred R₁ is CH₃. The most preferred R₃ is CH₂-Q, wherein Qis methoxy.

The most preferred aryl is phenyl. The most preferred halo is fluoro.

The most preferred compounds include:

-   (R)-2-acetamido-N-benzyl-3-methoxy-propionamide;-   O-methyl-N-acetyl-D-serine-m-fluorobenzyl-amide;-   O-methyl-N-acetyl-D-serine-p-fluorobenzyl-amide;-   N-acetyl-D-phenylglycine benzylamide;-   D-1,2-(N,O-dimethylhydroxylamino)-2-acetamide acetic acid    benzylamide;-   D-1,2-(O-methylhydroxylamino)-2-acetamido acetic acid benzylamide.

It is to be understood that the various combinations and permutations ofthe Markush groups of R₁, R₂, R₃, R and n described herein arecontemplated to be within the scope of the present invention. Moreover,the present invention also encompasses compounds and compositions whichcontain one or more elements of each of the Markush groupings in R₁, R₂,R₃, n and R and the various combinations thereof. Thus, for example, thepresent invention contemplates that R₁ may be one or more of thesubstituents listed hereinabove in combination with any and all of thesubstituents of R₂, R₃, and R with respect to each value of n.

The compounds utilized in the present invention may contain one or moreasymmetric carbons and may exist in racemic and optically active forms.The configuration around each asymmetric carbon can be either the D or Lform. It is well known in the art that the configuration around a chiralcarbon atoms can also be described as R or S in the Cahn-Prelog-Ingoldnomenclature system. All of the various configurations around eachasymmetric carbon, including the various enantiomers and diastereomersas well as racemic mixtures and mixtures of enantiomers, diastereomersor both are contemplated by the present invention.

In the principal chain, there exists asymmetry at the carbon atom towhich the groups R₂ and R₃ are attached. When n is 1, the compounds ofthe present invention is of the formula

wherein R, R₁, R₂, R₃, R₄, R₅, R₆, R′₆, R₇, R₈, R₅₀, Z and Y are asdefined previously.

As used herein, the term configuration shall refer to the configurationaround the carbon atom to which R₂ and R₃ are attached, even thoughother chiral centers may be present in the molecule. Therefore, whenreferring to a particular configuration, such as D or L, it is to beunderstood to mean the D or L stereoisomer at the carbon atom to whichR₂ and R₃ are attached. However, it also includes all possibleenantiomers and diastereomers at other chiral centers, if any, presentin the compound.

The compounds of the present invention are directed to all the opticalisomers, i.e., the compounds of the present invention are either theL-stereoisomer or the D-stereoisomer (at the carbon atom to which R₂ andR₃ are attached). These stereoisomers may be found in mixtures of the Land D stereoisomer, e.g., racemic mixtures. The D stereoisomer ispreferred.

More preferred is a compound of Formula (III) in the R configuration,preferably substantially enantiopure, wherein the substituent R isbenzyl which is unsubstituted or substituted with at least one halogroup, wherein R₃ is CH₂-Q, wherein Q is lower alkoxy containing 1-3carbon atoms and wherein R₁ is methyl. Preferably R is unsubstitutedbenzyl or benzyl substituted with at least one halo group which is afluoro group.

Depending upon the substituents, the present compounds may form additionsalts as well. All of these forms are contemplated to be within thescope of this invention including mixtures of the stereoisomeric forms.

The manufacture of the utilized compounds is described in U.S. Pat. Nos.5,378,729 and 5,773,475, the contents of both of which are incorporatedby reference.

The compounds utilized in the present invention are useful as such asdepicted in the Formulae (Ib) or/and (IIb) or can be employed in theform of salts in view of its basic nature by the presence of the freeamino group. Thus, the compounds of Formulae (Ib) or/and (IIb) formsalts with a wide variety of acids, inorganic and organic, includingpharmaceutically acceptable acids. The salts with therapeuticallyacceptable acids are of course useful in the preparation of formulationwhere enhanced water solubility is most advantageous.

These pharmaceutically acceptable salts have also therapeutic efficacy.These salts include salts of inorganic acids such as hydrochloric,hydroiodic, hydrobromic, phosphoric, metaphosphoric, nitric acid andsulfuric acids as well as salts of organic acids, such as tartaric,acetic, citric, malic, benzoic, perchloric, glycolic, gluconic,succinic, aryl sulfonic, (e.g., p-toluene sulfonic acids,benzenesulfonic), phosphoric, malonic, and the like.

The present invention is further directed to a method for theprevention, alleviation or/and treatment of a disease or condition asdescribed above in a mammal, including a human being, comprisingadministering at least one compound of Formulae (Ib) or/and (IIb).

It is preferred that the compound utilized in the present invention isused in therapeutically effective amounts.

The physician will determine the dosage of the present therapeuticagents which will be most suitable and it will vary with the form ofadministration and the particular compound chosen, and furthermore, itwill vary with the patient under treatment, the age of the patient, thetype of malady being treated. He will generally wish to initiatetreatment with small dosages substantially less than the optimum dose ofthe compound and increase the dosage by small increments until theoptimum effect under the circumstances is reached. When the compositionis administered orally, larger quantities of the active agent will berequired to produce the same effect as a smaller quantity givenparenterally. The compounds are useful in the same manner as comparabletherapeutic agents and the dosage level is of the same order ofmagnitude as is generally employed with these other therapeutic agents.

In a preferred embodiment, the compounds of the present invention areadministered in amounts ranging from about 1 mg to about 100 mg perkilogram of body weight per day, more preferred in amounts ranging fromabout 1 mg to about 10 mg per kilogram of body weight per day. Thisdosage regimen may be adjusted by the physician to provide the optimumtherapeutic response. Patients in need thereof may be treated with dosesof the compound of the present invention of at least 50 mg/day,preferably of at least 200 mg/day, more preferably of at least 300mg/day and most preferably of at least 400 mg/day. Generally, a patientin need thereof may be treated with doses at a maximum of 6 g/day, morepreferably a maximum of 1 g/day and most preferably a maximum of 600mg/day. In some cases, however, higher or lower doses may be needed.

In another preferred embodiment, the daily doses are increased until apredetermined daily dose is reached which is maintained during thefurther treatment.

In yet another preferred embodiment, several divided doses may beadministered daily. For example, three doses per day may beadministered, preferably two doses per day. It is more preferred toadminister a single dose per day.

In yet another preferred embodiment, an amount of the compounds of thepresent invention may be administered which results in a plasmaconcentration of 0.1 to 15 μg/ml (trough) and 5 to 18.5 μg/ml (peak),calculated as an average over a plurality of treated subjects.

The compounds of Formulae (Ib) or/and (IIb) may be administered in aconvenient manner, such as by oral, intravenous (where water soluble),intramuscular, intrathecal or subcutaneous routes. Oral or/and i.v.administration is preferred.

The pharmaceutical composition of the present invention may be preparedfor the treatment regimen as described above, in particular for thetreatment with doses as described above, to effect plasma concentrationsas described above, for administration periods or/and administrationroutes as specified in the embodiments of the present invention asdescribed above.

In another preferred embodiment, the method of the present invention asdescribed above for the treatment of a mammal including a human being inneed thereof comprises administering a compound of the present inventionin combination with administering a further active agent for theprevention, alleviation or/and treatment of a motoneuron disorder or/anda peripheral neuropathy. The compound of the present invention and thefurther active agent may be administered together, i.e. in a single doseform, or may be administered separately, i.e. in a separate dose form.Thus, the pharmaceutical composition of the present invention maycomprise a compound of the present invention as defined above and mayfurther comprise a further active agent for the prevention, alleviationor/and treatment of a motoneuron disorder or/and a peripheralneuropathy. The pharmaceutical composition may comprise a single doseform or may comprise a separate dose form comprising a first compositioncomprising a compound of the present invention as defined above and asecond composition comprising the further active agent.

The further active agent for the prevention, alleviation or/andtreatment of a motoneuron disorder or/and a peripheral neuropathy may beany suitable agent known to a person skilled in the art.

The compounds of the present invention may be used for the preparationof a pharmaceutical composition as described above.

The compounds of Formulae (Ib) or/and (IIb) may be orally administered,for example, with an inert diluent or with an assimilable ediblecarrier, or it may be enclosed in hard or soft shell gelatin capsules,or it may be compressed into tablets, or it may be incorporated directlyinto the fool of the diet. For oral therapeutic administration, theactive compound of Formulae (Ib) or/and (IIb) may be incorporated withexcipients and used in the form of ingestible tablets, buccal tablets,troches, capsules, elixirs, suspensions, syrups, wafers, and the like.Such compositions and preparations should contain at least 1% of activecompound of Formulae (Ib) or/and (IIb). The percentage of thecompositions and preparations may, of course, be varied and mayconveniently be between about 5 to about 80% of the weight of the unit.The amount of active compound of Formulae (Ib) or/and (IIb) in suchtherapeutically useful compositions is such that a suitable dosage willbe obtained. Preferred compositions or preparations according to thepresent invention contains between about 10 mg and 6 g active compoundof Formulae (Ib) or/and (IIb).

The tablets, troches, pills, capsules and the like may also contain thefollowing: A binder such as gum tragacanth, acacia, corn starch orgelatin; excipients such as dicalcium phosphate; a disintegrating agentsuch as corn starch, potato starch, alginic acid and the like; alubricant such as magnesium stearate; and a sweetening agent such assucrose, lactose or saccharin may be added or a flavoring agent such aspeppermint, oil of wintergreen, or cherry flavoring. When the dosageunit form is a capsule, it may contain, in addition to materials of theabove type, a liquid carrier.

Various other materials may be present as coatings or otherwise modifythe physical form of the dosage unit. For instance, tablets, pills, orcapsules may be coated with shellac, sugar or both. A syrup or elixirmay contain the active compound, sucrose as a sweetening agent, methyland propylparabens as preservatives, a dye and flavoring such as cherryor orange flavor. Of course, any material used in preparing any dosageunit form should be pharmaceutically pure and substantially non-toxic inthe amounts employed. In addition, the active compound may beincorporated into sustained-release preparations and formulations. Forexample, sustained release dosage forms are contemplated wherein theactive ingredient is bound to an ion exchange resin which, optionally,can be coated with a diffusion barrier coating to modify the releaseproperties of the resin.

The active compound may also be administered parenterally orintraperitoneally. Dispersions can also be prepared in glycerol, liquid,polyethylene glycols, and mixtures thereof and in oils. Under ordinaryconditions of storage and use, these preparations contain a preservativeto prevent the growth of microorganisms.

The pharmaceutical forms suitable for injectable use include sterileaqueous solutions (where water soluble) or dispersions and sterilepowders for the extemporaneous preparation of sterile injectablesolutions or dispersions. In all cases the form must be sterile and mustbe fluid to the extent that easy syringability exists. It must be stableunder the conditions of manufacture and storage and must be preservedagainst the contaminating action of microorganisms such as bacteria andfungi. The carrier can be a solvent or dispersion medium containing, forexample, water, ethanol, polyol (for example, glycerol, propyleneglycol, and liquid polyethylene glycol, and the like), suitable mixturesthereof, and vegetable oils. The proper fluidity can be maintained, forexample, by the use of a coating such as lecithin, by the maintenance ofthe required particle size in the case of dispersions and by the use ofsurfactants. The prevention of the action of microorganisms can bebrought about by various antibacterial and antifungal agents, forexample, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, andthe like. In many cases, it will be preferable to include isotonicagents, for example, sugars or sodium chloride. Prolonged absorption ofthe injectable compositions can be brought about by the use in thecompositions of agents delaying absorption, for example, aluminiummonostearate and gelatin.

Sterile injectable solutions are prepared by incorporating the activecompound in the required amount in the appropriate solvent with variousof the other ingredients enumerated above, as required, followed byfiltered sterilization. Generally, dispersions are prepared byincorporating the various sterilized active ingredient into a sterilevehicle which contains the basic dispersion medium and the requiredother ingredients from those enumerated above. In the case of sterilepowders for the preparation of sterile injectable solutions, thepreferred methods of preparation are vacuum drying the freeze-dryingtechnique plus any additional desired ingredient from previouslysterile-filtered solution thereof.

As used herein, “pharmaceutically acceptable carrier” includes any andall solvents, dispersion media, coatings, antibacterial and antifungalagent, isotonic and absorption delaying agents for pharmaceutical activesubstances as well known in the art. Except insofar as any conventionalmedia or agent is incompatible with the active ingredient, its use inthe therapeutic compositions is contemplated. Supplementary activeingredients can also be incorporated into the compositions.

It is especially advantageous to formulate parenteral compositions indosage unit form or ease of administration and uniformity of dosage.Dosage unit form as used herein refers to physically discrete unitssuited as unitary dosages for the mammalian subjects to be treated; eachunit containing a predetermined quantity of active material calculatedto produce the desired therapeutic effect in association with therequired pharmaceutical carrier. The specifics for the novel dosage unitforms of the invention are dictated by and directly dependent on (a) theunique characteristics of the active material an the particulartherapeutic effect to be achieved, and (b) the limitations inherent inthe art of compounding such as active material for the treatment ofdisease in living subjects having a diseased condition in which bodilyhealth is impaired as herein disclosed in detail.

The principal active ingredient is compounded for convenient andeffective administration in effective amounts with a suitablepharmaceutically acceptable carrier in dosage unit form as hereinbeforedescribed. A unit dosage form can, for example, contain the principalactive compound in amounts ranging from about 10 mg to about 6 g.Expressed in proportions, the active compound is generally present infrom about 1 to about 750 mg/ml of carrier. In the case of compositionscontaining supplementary active ingredients, the dosages are determinedby reference to the usual dose and manner of administration of the saidingredients.

As used herein the term “patient” or “subject” refers to a warm bloodedanimal, and preferably mammals, such as, for example, cats, dogs,horses, cows, pigs, mice, rats and primates, including humans. Thepreferred patient is a human.

The term “treat” refers to either relieving the pain associated with adisease or condition, to curing or alleviating the patient's disease orcondition or to prolonging survival.

The compounds of the present invention are administered to a patientsuffering from the aforementioned type of disorder in an effectiveamount. These amounts are equivalent to the therapeutically effectiveamounts described hereinabove.

The following example and figures show the properties of SPM 927 inimproving the motor coordination in and prolonging the survival of SODmutant mice.

The used substance was SPM 927 which is the synonym for Harkoseride. Thestandard chemical nomenclature is(R)-2-acetamide-N-benzyl-3-methoxypropionamide. The internationalnon-proprietary name of SPM 927 is lacosamide.

FIGURE LEGENDS

FIG. 1 shows that SPM 927 dose dependently prolongs life-span of SODmutant mice.

FIG. 2 shows that SPM 927 (30 mg/kg) attenuates motor impairment (gridperformance) of SOD mutant mice.

FIG. 3 shows that SPM 927 (10 mg/kg) attenuates motor impairment(latency of compound muscle action potential) of SOD mutant mice.

EXAMPLE

The Effects of SPM 927 in the SOD Mutant Mouse Model of AmyotrophicLateral Sclerosis (ALS)

This study demonstrates that chronic treatment with SPM 927 attenuatesmotor symptoms and prolongs survival time in a mouse model of ALS (theSOD mutant mouse). It is shown that SPM 927 treatment attenuates motorsymptoms including abnormalities in electrophysiological recordings(EMG) and prolongs survival time after symptom onset in the mouse model.

The present study investigates the effects of SPM 927 to protect or toreduce impairments observed in this ALS model. For this purposebehavioral measurements and EMGs are performed in SOD-G93A miceoverexpressing mutant human Cu,Zn SOD.

Materials and Methods

The transgenic mouse strain used for this study is G1H (Gurney et al.,1994). The animals begin to show signs of posterior limb weakness ataround 3 months of age and die at 4 months.

40 mice are included in the study and divided into 4 groups of 10 mice.

-   -   a SOD vehicle group    -   a SOD treated group (SPM 927 3 mg/kg)    -   a SOD treated group (SPM 927 10 mg/kg)    -   a SOD treated group (SPM 927 30 mg/kg)

Animals were weighed every day. The general status of the mice waschecked daily, especially for the presence of tremor, for skin aspectand for muscle wasting. EMG testing was performed once every week,starting on D70 of age until the death of the animals. The survival rateand the interval from symptom onset until death were recorded.

Motor Coordination Measurements

-   -   Rotarod test: this test evaluates the ability of the animal to        stay on a rotating dowel allowing evaluation of motor        coordination and proprioceptive sensitivity. The apparatus is a        3 cm diameter automated rod which turns at 12 rounds per minute        (Bioseb, Paris, France). The rotarod test measures how long the        mouse can maintain itself on the axle without falling. The test        is stopped after an arbitrary limit of 120 s. Should the animal        fall down before 120 s, the performance is recorded and two        additional trials are performed. The mean time of 3 trials is        calculated. A motor deficit is indicated by a decrease of        walking time.    -   Grid test: during the test the mice are placed on a grid        (length: 37 cm, width: 10.5 cm, mesh size: 1*1 cm) situated        above a plane support. The number of times the mice put their        paws through the grid is counted and serves as a measure for        motor coordination.    -   Hanging test: this test evaluates the ability of the animal to        hang on a wire. The apparatus is a wire stretched horizontally        40 cm above a table. The animal is attached to the wire by its        forepaws. The time needed by the animal to catch the string with        its hindpaws is recorded (60 s maximum) during three consecutive        trials.        Electrophysiological Measurements

Electromyographic recordings were performed using a Neuromatic 2000Melectromyography apparatus. During EMG the mice are anesthetized (60 mgkg-1, Imalgène@). The measured parameters are the amplitude and thelatency of the compound muscle action potential (CMAP). CMAP is measuredin gastrocnemius muscle after stimulation of the sciatic nerve. Areference electrode is inserted near the Achilles tendon and an activeneedle placed at the base of the tail. A ground needle is inserted onthe lower back of the mouse. The sciatic nerve is stimulated with asingle 0.2 ms pulse at supramaximal intensity (12.9 mA). The amplitude(mV) and the latency of the response (ms) are measured. The amplitude isindicative of the number of active motor units, while distal latencyreflects motor nerve conduction velocity.

Drug Administration

The animals were treated from day 60 (before the beginning of theclinical signs) until the animal's death. The treatment was administeredtwice daily intraperitoneally.

Data Analysis

A global analysis of the data was made using one factor or repeatedmeasures analysis of variance (ANOVA). The Fisher test or theStudent-Newman-Keuls t test was used to allow multiple comparisons ofindividual test groups with a control group or between paired groups.Intra-group analysis was performed to evaluate the variation ofperformance within each group.

Results

It was found that SPM 927:

-   -   prolongs survival time after onset of symptoms (FIG. 1)    -   alleviates motor symptoms in the rotarod-, grid- (FIG. 2) and        hanging test    -   attenuates EMG abnormalities (FIG. 3).

Conclusion

These results demonstrate that SPM 927 and related compounds are usefulfor the treatment of amyotrophic lateral sclerosis and for the treatmentof other motoneuron diseases including, but not limited to, progressivespinal muscular atrophies and progressive bulbar palsy. In addition, theresults show that SPM 927 and related compounds are active for thetreatment of peripheral neuropathies including, but not limited to,Guillain-Barré Syndrome or Charcot-Marie Tooth Syndrome.

References

ANDERSEN P M, NILSON P, ALA-HURULA V, KERANEN, M L, TARVAINEN I, HALTIAT, NILSSON L, BINZER M, FORSGREN L, MARKLUND S, (1995) Amyotrophiclateral sclerosis associated with homozygosity for an Asp90A1a mutationin Cu,Zn superoxide dismutase. Nature Genet. 10: 61-66.

BECKMAN J S, CARSON M, SMITH C D, KOPPENOL W H (1993) ALS, SOD andperoxynitrite. Nature 364: 584

BROWN R H, (1995) Superoxide dismutase in familial amyotrophicsclerosis: models for gain of function. Curr. Opin. Neurobiol. 5:841-846

DENG H X, HENTATI A, TAINER J A, IQBAL Z, CAYABYAB A, HUNG W Y, GETZOFFE D, HU P, HERZFELDT B, ROOS R P et al. (1993) Amyotrophic lateralsclerosis and structural defects in Cu,Zn superoxide dismutase. Science261: 1047-1051.

GURNEY M E, PU H, CHIU A Y, DAL CANTO M C, POLCHOW C Y, ALEXANDER D D,CALIENDO J, HENTATI A, KWON Y W, DENG H X et al. (1994) Motor neurondegeneration in mice that express a human Cu,Zn superoxide dismutasemutation. Science 264:1772-1775.

GURNEY M, CUTTING F B, ZHAI P, DOBLE A, TAYLOR C, ANDRUS P K, HALL E D(1996) Benefit of vitamin E riluzole, and gabapentin in a transgenicmodel of familial amyotrophic lateral sclerosis. Ann. Neurol.39:147-157.

GURNEY M E (1997) The use of transgenic mouse model of amyotrophiclateral sclerosis in preclinical drug studies. J. Neurol. Sci. 152:S67-73

MOHAJERI M H, FIGLEWICZ D A, BOHN M C (1998) Selective loss of alphamotoneurons innervating the medial gastrocnemius muscle in a model ifamyotrophic lateral sclerosis. Exp. Neurol. 150: 329-336.

ROSEN D R, SIDDIQUE T, PATTERSON D, FIGLEWICZ D A et al. (1993)Mutations in Cu/Zn superoxide dismutase gene are associated withfamilial amyotrophic lateral sclerosis. Nature 362: 59-62.

ROTHSTEIN J D, VAN KAMMEN M, LEVEY A L, MARTIN L J, KUNCL R W (1995)Selective loss of glial glutamate transporter GLT-1 in amyotrophiclateral sclerosis. Ann. Neurol. 38: 73-84.

YANG G, CHAN P H, CHE J, CARLSON E, CHEN S F, WEINSTEIN P, EPSTEIN C J,KAMII H (1994) Human copper-zinc superoxide dismutase transgenic miceare highly resistant to perfusion injury after focal cerebral ischemia.Stroke 25: 165-170.

1. Use of a compound having the Formula (Ib)

wherein R is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl,aryl lower alkyl, heterocyclic, heterocyclic lower alkyl, lower alkylheterocyclic, lower cycloalkyl or lower cycloalkyl lower alkyl, and R isunsubstituted or is substituted with at least one electron withdrawinggroup or/and at least one electron donating group; R₁ is hydrogen orlower alkyl, lower alkenyl, lower alkynyl, aryl lower alkyl, aryl,heterocyclic lower alkyl, lower alkyl heterocyclic, heterocyclic, lowercycloalkyl, lower cycloalkyl lower alkyl, each unsubstituted orsubstituted with at least one electron donating group or/and at leastone electron withdrawing group; R₂ and R₃ are independently hydrogen,lower alkyl, lower alkenyl, lower alkynyl, aryl lower alkyl, aryl, halo,heterocyclic, heterocyclic lower alkyl, lower alkyl heterocyclic, lowercycloalkyl, lower cycloalkyl lower alkyl, or Z-Y wherein R₂ and R₃ maybe unsubstituted or substituted with at least one electron withdrawinggroup or/and at least one electron donating group; and whereinheterocyclic in R₂ and R₃ is furyl, thienyl, pyrazolyl, pyrrolyl,methylpyrrolyl, imidazolyl, indolyl, thiazolyl, oxazolyl, isothiazolyl,isoxazolyl, piperidyl, pyrrolinyl, piperazinyl, quinolyl, triazolyl,tetrazolyl, isoquinolyl, benzofuryl, benzothienyl, morpholinyl,benzoxazolyl, tetrahydrofuryl, pyranyl, indazolyl, purinyl, indolinyl,pyrazolindinyl, imidazolinyl, imidazolindinyl, pyrrolidinyl, furazanyl,N-methylindolyl, methylfuryl, pyridazinyl, pyrimidinyl, pyrazinyl,pyridyl, epoxy, aziridino, oxetanyl, azetidinyl or, when N is present inthe heterocyclic, an N-oxide thereof; Z is O, S, S(O)_(a), NR₄, NR₆′ orPR₄ or a chemical bond; Y is hydrogen, lower alkyl, aryl, aryl loweralkyl, lower alkenyl, lower alkynyl, halo, heterocyclic, heterocycliclower alkyl, lower alkyl heterocyclic and Y may be unsubstituted orsubstituted with at least one electron donating group or/and at leastone an electron withdrawing group, wherein heterocyclic has the samemeaning as in R₂ or R₃ and, provided that when Y is halo, Z is achemical bond, or ZY taken together is NR₄NR₅R₇, NR₄OR₅, ONR₄R₇, OPR₄R₅,PR₄OR₅, SNR₄R₇, NR₄SR₇, SPR₄R₅, PR₄SR₇, NR₄PR₅R₆, PR₄NR₅R₇, or N⁺R₅R₆R₇,

R₆′ is hydrogen, lower alkyl, lower alkenyl, or lower alkynyl which maybe unsubstituted or substituted with at least one electron withdrawinggroup or/and at least one electron donating group; R₄, R₅ and R₆ areindependently hydrogen, lower alkyl, aryl, aryl lower alkyl, loweralkenyl, or lower alkynyl, wherein R₄, R₅ and R₆ may independently beunsubstituted or substituted with at least one electron withdrawinggroup or/and at least one electron donating group; and R₇ is R₆ or COOR₈or COR₈, which R₇ may be unsubstituted or substituted with at least oneelectron withdrawing group or/and at least one electron donating group;R₈ is hydrogen or lower alkyl, or aryl lower alkyl, and the aryl oralkyl group may be unsubstituted or substituted with at least oneelectron withdrawing group or/and at least one electron donating group;and n is 1-4; and a is 1-3, or of a pharmaceutically acceptable saltthereof, for the preparation of a pharmaceutical composition useful forthe prevention, alleviation or/and treatment of motoneuron disordersor/and peripheral neuropathies.
 2. Use according to claim 1, wherein thedisorder is amyotrophic lateral sclerosis (ALS).
 3. Use according toclaim 1 wherein one of R₂ and R₃ is hydrogen.
 4. Use according to claim1 wherein n is
 1. 5. Use according to claim 1 wherein one of R₂ and R₃is hydrogen and n is
 1. 6. Use according to claim 1 wherein R is aryllower alkyl and R₁ is lower alkyl.
 7. Use according to claim 1 whereinR₂ and R₃ are independently hydrogen, lower alkyl, or ZY; Z is O, NR₄ orPR₄; Y is hydrogen or lower alkyl or ZY is NR₄NR₅R₇, NR₄OR₅, ONR₄R₇,


8. Use according to claim 7 wherein R₂ is hydrogen and and R₃ is loweralkyl, or ZY; Z is O, NR₄ or PR₄; Y is hydrogen or lower alkyl; ZY isNR₄NR₅ NR₇, NR₄OR₅, ONR₄R₇,


9. Use according to claim 1 wherein R₂ is hydrogen and R₃ is loweralkyl, which may be substituted or unsubstituted with at least oneelectron donating group or/and at least one electron withdrawing group,NR₄OR₅, or ONR₄R₇.
 10. Use according to claim 1 wherein R₃ is loweralkyl which is unsubstituted or substituted with hydroxy or loweralkoxy,NR₄OR₅ or ONR₄R₇, wherein R₄, R₅ and R₇ are independently hydrogen orlower alkyl, R is aryl lower alkyl, which aryl group may beunsubstituted or substituted with at least one electron withdrawinggroup and R₁ is lower alkyl.
 11. Use according to claim 1 wherein arylis phenyl and is unsubstituted or substituted with halo.
 12. Useaccording to claim 1 wherein the compound is(R)-2-acetamido-N-benzyl-3-methoxy-propionamide;O-methyl-N-acetyl-b-serine-m-fluorobenzylamide;O-methyl-N-acetyl-D-serine-p-fluorobenzylamide;N-acetyl-D-phenylglycinebenzylamide; D-1,2-(N,O-dimethylhydroxylamino)-2-acetamide acetic acid benzylamide; orD-1,2-(O-methylhydroxylamino)-2-acetamido acetic acid benzylamide. 13.Use of claim 1 wherein the compound has the Formula (IIb)

wherein Ar is phenyl which is unsubstituted or substituted with at leastone halo group; R₃ is CH₂-Q, wherein Q is lower alkoxy containing 1-3carbon atoms and R₁ is lower alkyl containing 1-3 carbon atoms or of apharmaceutically acceptable salt thereof.
 14. Use according to claim 13wherein Ar is unsubstituted phenyl.
 15. Use according to claim 13wherein halo is fluoro.
 16. Use according to claim 13 wherein R₃ isCH₂-Q, wherein Q is alkoxy containing 1-3 carbon atoms and Ar isunsubstituted phenyl.
 17. Use of claim 1 wherein the compund is in the Rconfiguration and has the formula

wherein R is benzyl which is unsubstituted or substituted with at leastone halo group; R₃ is CH₂ -Q, wherein Q is lower alkoxy containing 1-3carbon atoms and R₁ is methyl or a pharmaceutically acceptable saltthereof.
 18. Use according to claim 17 which is substantiallyenantiopure.
 19. Use according to claim 17 wherein R is unsubstitutedbenzyl.
 20. Use according to claim 17 wherein halo is fluoro.
 21. Useaccording to claim 17 wherein R₃ is CH₂-Q, wherein Q is alkoxycontaining 1-3 carbon atoms and R is unsubstituted benzyl.
 22. Useaccording to claim 1, wherein the compound of Formula (Ib) is(R)-2-Acetamido-N-benzyl-3-methoxypropionamide or a pharmaceuticallyacceptable salt thereof.
 23. Use according to claim 22 wherein thecompund is substantially enantiopure.
 24. Use according to claim 1,wherein the pharmaceutical composition is prepared for treatment withdoses of the compound at least of 100 mg/day, preferably at least of 200mg/day, more preferably at least of 300 mg/day, most preferably at leastof 400 mg/day.
 25. Use according to claim 1, wherein the pharmaceuticalcomposition is prepared for treatment with doses of the compound at amaximum of 6 g/day, more preferably at a maximum of 1 g/day and mostpreferably at a maximum of 600 mg/day.
 26. Use according to claim 1,wherein the pharmaceutical composition is prepared for treatment withincreasing daily doses until a predetermined daily dose is reached whichis maintained during the further treatment.
 27. Use according to claim1, wherein the pharmaceutical composition is prepared for treatment inthree doses per day, preferably two doses per day, more preferably in asingle dose per day.
 28. Use according to claim 1, wherein thepharmaceutical composition is prepared for an administration resultingin a plasma concentration of 0.1 to 15 μg/ml (trough) and 5 to 18.5μg/ml (peak), calculated as an average over a plurality of treatedsubjects.
 29. Use according to claim 1, wherein the pharmaceuticalcomposition is prepared for oral or i.v. administration.
 30. Useaccording to claim 1, wherein the pharmaceutical composition furthercomprises an active agent for the prevention, alleviation or/andtreatment of motoneuron disorders or/and peripheral neuropathies. 31.Use according to claim 30 wherein the pharmaceutical compositioncomprises a single dose form, or comprises a separate dose formcomprising a first composition comprising said compound of Formula (Ib)and a second composition comprising the further active agent.
 32. Useaccording to claim 1 wherein the pharmaceutical composition is preparedfor administration in mammals.
 33. Use according to claim 33 wherein thepharmaceutical composition is prepared for administration in humans. 34.A pharmaceutical composition comprising (a) a compound as defined inclaim 1, and (b) a further active agent for the prevention, alleviationor/and treatment of motoneuron disorders or/and peripheral neuropathies.35. The pharmaceutical composition according to claim 34 which is asingle dose form, or comprises a separate dose form comprising a firstcomposition comprising said compound of Formula (Ib) and a secondcomposition comprising the further active agent (b).